Dpp iv inhibitor formulations

ABSTRACT

The present invention relates to pharmaceutical compositions of DPP IV inhibitors with an amino group, their preparation and their use to treat diabetes mellitus.

This application is a continuation of U.S. application Ser. No.11/744,701, filed May 4, 2007, which claims priority of EP 06 009 201,filed Mary 4, 2006, each of which is hereby incorporated by reference inits entirety.

1. FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of selectedDPP IV inhibitors, their preparation and their use to treat selectedmedical conditions.

2. DESCRIPTION OF THE PRIOR ART

The enzyme DPP-IV (dipeptidyl peptidase IV) also known as CD26 is aserine protease known to lead to the cleavage of a dipeptide from theN-terminal end of a number of proteins having at their N-terminal end aprolin or alanin residue. Due to this property DPP-IV inhibitorsinterfere with the plasma level of bioactive peptides including thepeptide GLP-1 and are considered to be promising drugs for the treatmentof diabetes mellitus.

DETAILED DESCRIPTION OF THE INVENTION

In attempts to prepare pharmaceutical compositions of selected DPP-IVinhibitors it has been observed, that the DPP-IV inhibitors with aprimary or secondary amino group show incompatibilities, degradationproblems, or extraction problems with a number of customary excipientssuch as microcrystalline cellulose, sodium starch glycolate,croscarmellose sodium, tartaric acid, citric acid, glucose, fructose,saccharose, lactose, maltodextrines. Though the compounds themselves arevery stable, they react with many excipients used in solid dosage formsand with impurities of excipients, especially in tight contact providedin tablets and at high excipient/drug ratios. The amino group appears toreact with reducing sugars and with other reactive carbonyl groups andwith carboxylic acid functional groups formed for example at the surfaceof microcrystalline cellulose by oxidation. These unforeseendifficulties are primarily observed in low dosage ranges which arerequired due to the surprising potency of the selected inhibitors. Thus,pharmaceutical compositions are required so solve these technicalproblems associated with the unexpected potency of selected DPP-IVinhibitor compounds.

A pharmaceutical composition according to the present invention isintended for the treatment of to achieve glycemic control in a type 1 ortype 2 diabetes mellitus patient and comprises a DPP-IV inhibitor withan amino group, especially a free or primary amino group, as an activeingredient, a first and second diluent, a binder, a disintegrant and alubricant. An additional disintegrant and an additional glidant are afurther option. Additionally the compositions can be used to treatrheumatoid arthritis, obesity and osteoporosis as well as to supportallograft transplantation.

Diluents suitable for a pharmaceutical composition according to theinvention are cellulose powder, dibasic calciumphosphate anhydrous,dibasic calciumphosphate dihydrate, erythritol, low substitutedhydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.Among those diluents mannitol and pregelatinized starch are preferred.

Diluents preferred as the second diluent are the above mentioneddiluents pre-gelatinized starch and low-substitutedhydroxypropylcellulose (L-HPC) which show additional binder properties.

Lubricants suitable for a pharmaceutical composition according to theinvention are talc, polyethyleneglycol, calcium behenate, calciumstearate, hydrogenated castor oil or magnesium stearate. The preferredlubricant is magnesium stearate.

Binders suitable for a pharmaceutical composition according to theinvention are copovidone (copolymerisates of vinylpyrrolidon with othervinylderivates), hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone),pregelatinized starch, low-substituted hydroxypropylcellulose (L-HPC),copovidone and pregelatinized starch being preferred.

The above mentioned binders pregelatinized starch and L-HPC showadditional diluent and disintegrant properties and can also be used asthe second diluent or the disintegrant.

Disintegrants suitable for a pharmaceutical composition according to thepresent invention are corn starch, crospovidone, low-substitutedhydroxypropylcellulose (L-HPC) or pregelatinized starch, corn starchbeing preferred.

As an optional glidant colloidal silicon dioxide can be used.

An exemplary composition according to the present invention comprisesthe diluent mannitol, pregelatinized starch as a diluent with additionalbinder properties, the binder copovidone, the disintegrant corn starch,and magnesium stearate as the lubricant.

Dosage forms prepared with a pharmaceutical compositions according tothe present invention contain active ingredients in dosage ranges of0.1-100 mg. Preferred dosages are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

Typical pharmaceutical compositions comprise (% by weight)

0.5-20%  active ingredient 40-88%  diluent 1, 3-40% diluent 2,  1-5%binder, 5-15% disintegrant, and 0.1-4%  lubricant.

Preferred pharmaceutical compositions comprise (% by weight)

0.5-7% active ingredient 50-75%  diluent 1,  5-15% diluent 2,  2-4%binder,  8-12% disintegrant, and 0.5-2% lubricant

The pharmaceutical compositions according to the invention are intendedfor oral use and can be used in the dosage form of a capsule, a tabletor a film-coated tablet. Typically the film coat represents 2-4%,preferably 3% of the composition and comprises a film-forming agent, aplasticizer, a glidant and optionally one or more pigments. An exemplarycoat composition may comprise hydroxypropylmethyl-cellulose (HPMC),polyethylene glycol (PEG), talc, titanium dioxide and optionally ironoxide.

Preferred active ingredients in the context of the present invention areDPP-IV inhibitors with a primary amino group and salts thereof such asany DPP-IV inhibitor and salt thereof defined by formula (I)

or formula (II)

wherein R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl],(quinoxalin-6-yl)methyl, (4-Methyl-quinazolin-2-yl)methyl,2-Cyano-benzyl, (3-Cyano-quinolin-2-yl)methyl,(3-Cyano-pyridin-2-yl)methyl, (4-Methyl-pyrimidin-2-yl)methyl, or(4,6-Dimethyl-pyrimidin-2-yl)methyl, and R2 is3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino.

Preferred DPP IV inhibitor compounds are the following compounds andsalts thereof:

-   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(142):

-   -   1-[([1,5]naphthyridin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2(252)):

-   -   1-[(Quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2(80)):

-   -   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one        (compare WO 2004/050658, example 136):

-   -   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyln-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine        (compare WO 2006/029769, example 2(1)):

-   -   1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(30)):

-   -   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(39)):

-   -   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine        (compare WO 2006/029769, example 2(4)):

-   -   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(52)):

-   -   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(81)):

-   -   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(82)):

-   -   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1(83)):

To prepare compositions according to the invention a granulate can beprepared by a wet granulation process. Alternative methods forgranulation of active ingredient and excipients with a granulationliquid are fluid bed granulation or one-pot granulation.

In the wet granulation process the granulation liquid is a solvent suchas water, ethanol, methanol, isopropanol, acetone, preferably purifiedwater, and contains a binder such as copovidone. The solvent is avolatile component, which does not remain in the final product. Theactive ingredient and the other excipients with exception of thelubricant are premixed and granulated with the aqueous granulationliquid using a high shear granulator. The wet granulation step isfollowed by an optional wet sieving step, drying and dry sieving of thegranules. For example a fluid bed dryer can then be used for drying.

The dried granules are sieved through an appropriate sieve. Afteraddition of the other excipients with exception of the lubricant themixture is blended in a suitable conventional blender such as a freefall blender followed by addition of the lubricant such as magnesiumstearate and final blending in the blender.

Thus an exemplary wet granulation process for the preparation of apharmaceutical composition according to the present invention comprises

-   a. dissolving a binder such as copovidone in a solvent such as    purified water at ambient temperature to produce a granulation    liquid;-   b. blending a DPP-IV inhibitor, a diluent, and a disintegrant in a    suitable mixer, to produce a pre-mix;-   c. moistening the pre-mix with the granulation liquid and    subsequently granulating the moistened pre-mix for example in a high    shear mixer;-   d. optionally sieving the granulated pre-mix through a sieve with a    mesh size of at least 1.0 mm and preferably 3 mm;-   e. drying the granulate at about 40-75° C. and preferably 55-65° C.    inlet air temperature for example in a fluid bed dryer until the    desired loss on drying value in the range of 1-5% is obtained;-   f. delumping the dried granulate for example by sieving through a    sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm; and-   g. adding preferably sieved lubricant to the granulate for final    blending for example in a cube mixer.

In an alternative process part of the exipients such as part of adisintegrant (e.g. corn starch) or a diluent (e.g. pregelatinizedstarch) or an additional disintegrant (crospovidone) can be addedextragranular prior to final blending of step g.

In another alternative version of the process the granulate produced insteps a to e is produced in a one pot high shear granulation process andsubsequent drying in a one pot granulator.

For the preparation of capsules the final blend is further filled intocapsules.

For the preparation of tablets or tablet cores the final blend isfurther compressed into tablets of the target tablet core weight withappropriate size and crushing strength, using an appropriate tabletpress.

For the preparation of film-coated tablets a coating suspension isprepared and the compressed tablet cores are coated with the coatingsuspension to a weight gain of about 2-4%, preferably about 3%, using astandard film coater. The film-coating solvent is a volatile component,which does not remain in the final product. To reduce the requiredamount of lubricant in the tablets it is an option to use an externallubrication system.

EXAMPLES Example 1 Formulation for Direct Compression

An active DPP IV inhibitor ingredient with a primary amino group and allother excipients with exception of magnesium stearate are blended in ahigh shear blender. This pre-mix is sieved through a 1 mm sieve. Afteraddition of magnesium stearate the pre-mix is blended in a free fallblender to produce the final blend. The final blend is compressed intotablets using a suitable tablet press. The following compositions can beobtained:

Component mg/tablet %/tablet mg/tablet %/tablet Active ingredient 1.0002.000 2.500 2.000 Mannitol 43.250 86.500 108.125 86.500 Pregelatinizedstarch 5.000 10.000 12.500 10.000 Magnesium stearate 0.750 1.500 1.8751.500 Total 50.000 100.000 125.000 100.000

Component mg/tablet %/tablet mg/tablet %/tablet Active ingredient 5.0002.000 10.000 2.000 Mannitol 216.250 86.500 432.500 86.500 Pregelatinizedstarch 25.000 10.000 50.000 10.000 Magnesium stearate 3.750 1.500 7.5001.500 Total 250.000 100.000 500.000 100.000

Example 2 Alternative Formulation for Direct Compression

An active DPP IV inhibitor ingredient with a primary amino group and allother excipients with exception of magnesium stearate are blended in ahigh shear blender. This pre-mix is sieved through a 1 mm sieve. Afteraddition of magnesium stearate the pre-mix is blended in a free fallblender to produce the final blend. The final blend is compressed intotablets using a suitable tablet press. The following compositions can beobtained:

Component mg/tablet %/tablet mg/tablet %/tablet Active ingredient 1.0001.667 0.500 0.833 Dibasic 46.400 77.333 46.900 78.177 calciumphosphate,anhydrous Low-substituted 12.000 20.000 12.000 20.000hydroxypropylcellulose Magnesium stearate 0.600 1.000 0.600 1.000 Total60.000 100.000 60.000 100.000

Component mg/tablet %/tablet mg/tablet %/tablet Active ingredient 10.0001.667 10.000 2.222 Dibasic 464.000 77.333 344.000 76.788calciumphosphate, anhydrous Low-substituted 120.000 20.000 90.000 20.000hydroxypropylcellulose Magnesium stearate 6.000 1.000 6.000 1.000 Total600.000 100.000 450.000 100.000

Example 3 Tablet Formulation

Copovidone is dissolved in purified water at ambient temperature toproduce a granulation liquid. An active DPP IV inhibitor ingredient witha primary amino group, mannitol and part of the pregelatinized starchare blended in a suitable mixer, to produce a pre-mix. The pre-mix ismoistened with the granulation liquid and subsequently granulated. Themoist granulate is optionally sieved through a sieve with a mesh size of1.6-3.0 mm. The granulate is dried at 55° C. in a suitable dryer to aresidual moisture content corresponding to 2-5% loss on drying. Thedried granulate is sieved through a sieve with a mesh size of 1.0 mm.The granulate is blended with part of the pregelatinized starch in asuitable mixer. Magnesium stearate is added to this blend after passingthrough a 1.0 mm sieve for delumping. Subsequently the final blend isproduced by final blending in a suitable mixer and compressed intotablets. The following tablet composition can be obtained:

Component mg/tablet %/tablet Active ingredient 10.000 1.667Pregelatinized starch 210.000 35.000 Mannitol 236.000 39.333 Copovidone18.000 3.000 Total (granulate) 474.000 79.000 Pregelatinized starch120.000 20.000 Magnesium stearate 6.000 1.000 Total 600.000 100.000

Example 4 Coated Tablet Formulation

Copovidone is dissolved in purified water at ambient temperature toproduce a granulation liquid. An active DPP IV inhibitor ingredient witha primary amino group, mannitol, pregelatinized starch and corn starchare blended in a suitable mixer to produce the pre-mix. The pre-mix ismoistened with the granulation liquid and subsequently granulated usinga high shear mixer. The moist granulate is optionally sieved through asieve with a mesh size of 1.6-3.0 mm. The granulate is dried at about60° C. in a fluid bed dryer until a loss on the drying value of 2-4% isobtained. The Final Blend is compressed into tablet cores.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titaniumdioxide and iron oxide are suspended in purified water in a suitablemixer at ambient temperature to produce a coating suspension. The tabletcores are coated with the coating suspension to a weight gain of about3% to produce film-coated tablets. The following tablet compositions canbe obtained:

Component mg mg mg mg mg Active ingredient 0.500 1.000 2.500 5.00010.000 Mannitol 67.450 66.950 65.450 130.900 125.900 Pregelatinizedstarch 9.000 9.000 9.000 18.000 18.000 Corn starch 9.000 9.000 9.00018.000 18.000 Copovidone 2.700 2.700 2.700 5.400 5.400 Magnesiumstearate 1.350 1.350 1.350 2.700 2.700 Total Mass 90.000 90.000 90.000180.000 180.000 (tablet core) HPMC 1.500 1.500 1.500 2.500 2.500 PEG0.150 0.150 0.150 0.250 0.250 Titanium dioxide 0.750 0.750 0.750 1.2501.250 Talc 0.525 0.525 0.525 0.875 0.875 Iron oxide, yellow 0.075 0.0750.075 0.125 0.125 Total Mass 93.000 93.000 93.000 185.000 185.000(coated tablet)

Example 5 Tablet Formulation

Copovidone is dissolved in purified water at ambient temperature toproduce a granulation liquid. An active DPP IV inhibitor ingredient witha primary amino group, mannitol and pregelatinized starch are blended ina suitable mixer to produce a pre-mix. The pre-mix is moistened with thegranulation liquid and subsequently granulated. The moist granulate isoptionally sieved through a suitable sieve. The granulate is dried atabout 50° C. in a suitable dryer until a loss on drying value of 3-5% isobtained. The dried granulate is sieved through a sieve with a mesh sizeof 1.0 mm.

Magnesium stearate is passed through a 1.0 mm sieve and added to thegranulate. Subsequently the final blend is produced by final blending ina suitable blender and the final blend is compressed into tablets. Thefollowing tablet compositions can be obtained:

Component mg mg mg mg mg Active ingredient 0.500 1.000 2.500 5.00010.000 Mannitol 27.500 27.000 67.500 135.000 130.000 Pregelatinizedstarch 20.000 20.000 50.000 100.000 100.000 Copovidone 1.500 1.500 3.7507.500 7.500 Magnesium stearate 0.500 0.500 1.250 2.500 2.500 Totaltablet mass 50.000 50.000 125.000 250.000 250.000

Example 6 Tablet Formulation Variants

Copovidone is dissolved in purified water at ambient temperature toproduce a granulation liquid. An active DPP IV inhibitor ingredient witha primary amino group and a part of mannitol, pregelatinized starch andcorn starch are blended in a suitable mixer, to produce a pre-mix. Thepre-mix is moistened with the granulation liquid and subsequentlygranulated. The moist granulate is sieved through a suitable sieve. Thegranulate is dried at about 60° C. inlet air temperature in a fluid beddryer until a loss on drying value of 1-4% is obtained. The driedgranulate is sieved through a sieve with a mesh size of 1.0 mm.

Magnesium stearate is passed through a sieve for delumping and added tothe granulate. Additionally the remaining part of the exipients areadded extragranular at this process step. Subsequently the final blendis produced by final blending in a suitable blender and compressed intotablet cores.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titaniumdioxide and iron oxide are suspended in purified water in a suitablemixer at ambient temperature to produce a coating suspension. The tabletcores are coated with the coating suspension to a weight gain of about3% to produce film-coated tablets. The following formulation variantscan be obtained:

Example 6.1 Formulation Variants with Extragranular Excipients

Formulation E Formulation F Component mg/Tablet %/Tablet mg/Tablet%/Tablet Active ingredient 1.000 1.111 1.000 1.111 Mannitol 23.30025.889 66.950 74.389 Pregelatinized starch 4.500 5.000 4.500 5.000 Cornstarch 4.500 5.000 4.500 5.000 Copovidone 1.350 1.500 2.700 3.000 Total(granulate) 34.650 38.500 79.650 88.500 Corn starch 4.500 5.000 4.5005.000 Pregelatinized starch 4.500 5.000 4.500 5.000 Mannitol 45.00050.000 Magnesium stearate 1.350 1.500 1.350 1.500 Total (tablet core)90.000 100.000 90.000 100.000

Example 6.2 Formulation Variants with Additional ExtragranularDisintegrant

Component mg mg mg mg mg Active ingredient 0.500 1.000 2.500 5.00010.000 Mannitol 67.450 66.950 65.450 130.900 125.900 Pregelatinizedstarch 9.000 9.000 9.000 18.000 18.000 Corn starch 9.000 9.000 9.00018.000 18.000 Copovidone 2.700 2.700 2.700 5.400 5.400 Total Mass 88.65088.650 88.650 177.300 177.300 (granulate) Magnesium stearate 1.350 1.3501.350 2.700 2.700 Crospovidone 2.000 2.000 2.000 4.000 4.000 Total Mass92.000 92.000 92.000 184.000 184.000 (tablet core) HPMC 1.500 1.5001.500 2.500 2.500 PEG 0.150 0.150 0.150 0.250 0.250 Titanium dioxide0.750 0.750 0.750 1.250 1.250 Talc 0.525 0.525 0.525 0.875 0.875 Ironoxide, yellow 0.075 0.075 0.075 0.125 0.125 Total Mass 95.000 95.00095.000 189.000 189.000 (coated tablet)

Example 6.3 High Dose Formulations D

Component mg/tablet %/tablet mg/tablet %/tablet Active ingredient 25.00027.778 50.000 27.778 Mannitol 40.700 45.222 81.400 45.222 Pregelatinizedstarch 9.000 10.000 18.000 10.000 Corn starch 9.000 10.000 18.000 10.000Copovidone 2.700 3.000 5.400 3.000 Total (granulate) 86.400 96.000172.800 96.000 Crospovidone 2.700 3.000 5.400 3.000 Magnesium stearate0.900 1.000 1.800 1.000 Total (tablet core) 90.000 100.000 180.000100.000 Hydroxypropyl 1.500 1.667 2.500 1.389 methylcellulosePolyethylene glycol 0.150 0.167 0.250 0.139 Titanium dioxide 0.750 0.8331.250 0.694 Talcum 0.525 0.583 0.875 0.486 Iron oxide yellow 0.075 0.0830.125 0.069 Total 93.000 103.333 185.000 102.778 (film-coated tablet)

1. A pharmaceutical composition comprising as an active ingredient a DPPIV inhibitor compound of formula

in an amount of 0.5 mg, 1 mg, 2.5 mg, 5 mg or 10 mg, or a salt thereof,a first diluent, a second diluent, a binder, a disintegrant and alubricant, wherein the first diluent is mannitol, the second diluent ispregelatinized starch, the binder is copovidone, the disintegrant iscorn starch, and the lubricant is magnesium stearate; and wherein theDPP IV inhibitor compound is present in an amount 0.5-20% based on thetotal weight of DPP IV inhibitor compound, first diluent, seconddiluent, binder, disintegrant and lubricant.
 2. The pharmaceuticalcomposition of claim 1 further comprising an additional disintegrant. 3.The pharmaceutical composition of claim 2, wherein the additionaldisintegrant is crospovidone.
 4. The pharmaceutical composition of claim1 further comprising a glidant.
 5. The pharmaceutical composition ofclaim 4, wherein the glidant is colloidal silicon dioxide.
 6. Thepharmaceutical composition of claim 1 comprising 40-88%  diluent 1,3-40% diluent 2,  1-5% binder, 5-15% disintegrant, and 0.1-4%  lubricant


7. The pharmaceutical composition of claim 1 comprising 0.5-7% activeingredient 50-75%  diluent 1,  5-15% diluent 2,  2-4% binder,  8-12%disintegrant, and 0.5-2% lubricant


8. The pharmaceutical composition according to claim 1 in the dosageform of a capsule, a tablet, or a film-coated tablet.
 9. Thepharmaceutical composition of claim 8 comprising 2-4% film coat.
 10. Thepharmaceutical composition of claim 9, wherein the film coat comprises afilm-forming agent, a plasticizer, a glidant and optionally one or morepigments.
 11. The pharmaceutical composition of claim 10, wherein thefilm coat comprises hydroxypropylmethylcellulose (HPMC), polyethyleneglycol (PEG), talc, titanium dioxide and iron oxide.
 12. A process forthe preparation of a pharmaceutical composition according to claim 1comprising a. dissolving the binder in a solvent to produce agranulation liquid; b. blending the DPP-IV inhibitor, a diluent, and thedisintegrant to produce a pre-mix; c. moistening the pre-mix with thegranulation liquid and subsequently granulating the moistened pre-mix;d. optionally sieving the granulated pre-mix through a sieve with a meshsize of at least 1.0 mm; e. drying the granulate at about 40-75° C.until the desired loss on drying value in the range of 1-5% is obtained;f. sieving the dried granulate through a sieve with a mesh size of atleast 0.6 mm; g. adding the lubricant to the granulate for finalblending.
 13. The process according to claim 12 further comprising h.compressing the final blend into tablet cores; i. preparing a coatingsuspension; j. coating the tablet cores with the coating suspension to aweight gain of about 2-4% to produce film-coated tablets.
 14. Theprocess according to claim 12, wherein part of the excipients are addedextragranular prior to the final blending of step g.
 15. The processaccording to claim 12, wherein the granulate produced in steps a-e isproduced in a one pot high shear granulation process and subsequentdrying in a one pot granulator.
 16. The pharmaceutical compositionaccording to claim 1, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis comprised in an amount of 5 mg.
 17. The pharmaceutical compositionaccording to claim 16 in the form of a capsule, a tablet, or afilm-coated tablet.
 18. The pharmaceutical composition of claim 16,wherein the composition is in the form of a film-coated tablet, andwherein the film coat comprise 2-4% wt % based the weight of theuncoated tablet.
 19. The pharmaceutical composition of claim 18, whereinthe film coat comprises a film-forming agent, a plasticizer, a glidantand optionally one or more pigments.
 20. The pharmaceutical compositionof claim 19, wherein the film coat compriseshydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc,titanium dioxide and iron oxide.
 21. The pharmaceutical compositionaccording to claim 16, which is an oral dosage form in the form of atablet.
 22. The pharmaceutical composition according to claim 16, whichis an oral dosage form in form of a film-coated tablet.